Prostatic carcinoma is the leading malignancy in human males in terms of incidence and the second leading cause of cancer deaths in men. While a majority of prostatic carcinomas remain dormant for a long period of time, a significant minority of them displays rapid growth and invasive characteristics. The mechanisms responsible for the latent growth of tumors in a majority of cases and for rapid progression in a minority of cases have not been identified. It has been suggested that tumors with greater neuroendocrine cell populations may display autonomous growth, androgen-independence and increased invasiveness. See Cohen et al., Neuroendocrine Differentiation in Prostatic Adenocarcinoma and Its Relationship to Tumor Progression, CANCER 74:1899-1903 (1994); Huang et al., Relation Between Neuroendocrine Expression of Prostatic Carcinoma and Prognosis, CHUNG. HUA. I. HSUEH. TSA. CHIH. 74:23-5, 62 (1994); Kadmon et al., Elevated Plasma Chromogranin-A Concentrations in Prostatic Carcinoma, J. UROL. 146:358-61 (1991).
The major therapeutic approach for the treatment of prostate cancer is androgen-deprivation through chemical means or surgical removal of the tumor. Indeed, patients with advanced prostatic carcinoma (PC) as well as experimental in vitro PC models respond largely to various methods of androgen deprivation such as orchiectomy, administration of estrogens, anti-androgens and analogs of gonadotropin-releasing hormone (LH-RH). However, a significant population of these individuals also exhibits tumor relapse in 18-36 months. Relapse and the subsequent spread of prostate cancer cells have been associated with androgen-insensitivity. Therefore, a possible cause of relapse, local invasion, and metastasis is the proliferation of androgen-insensitive clones. That is, those cancer cells which require androgens for growth die when they are deprived of androgens during therapy, but those aggressive androgen-independent prostatic carcinoma cells (“AIPC cells”) continue to proliferate even in the absence of androgens. Two areas of prostate cancer biology currently under intense investigation include: (1) the cause of relapse of prostate carcinoma in patients who initially respond to androgen deprivation treatments; and (2) the early detection of prostatic carcinomas that will become metastatic. Once the relapse occurs, few treatment options are available and eventually the patient dies from the disease. Continued proliferation of clonally derived AIPC tumor cells is believed to be the underlying cause of the relapse, as metastatic tumors are frequently found to be androgen-independent. Although AIPC cells are by definition independent from influence by androgens, there are neuroendocrine and other growth factors, which can stimulate their growth. Tumor cells are known to express distinct markers at the very early stage of transformation. Several tumor markers have been identified and have been used to identify either the presence of malignancy and/or the severity of the malignancy. For example, prostate-specific antigen (PSA) has been identified and used for the diagnosis of prostate cancer. Although PSA has been used as a marker for PC for several years, current evidence suggests that serum PSA levels: (1) do not always correlate with progression of the disease; (2) are not expressed in a small but significant number of aggressive PCs which therefore are undetected by PSA screening; and (3) do not predict the clinical nature of the tumor, i.e., even if the tumor is detected early, PSA screening does not predict whether the tumor will be dormant and therefore relatively harmless, or will be aggressive requiring immediate clinical intervention. Although PSA is used as a diagnostic marker for PC, neither PSA nor other serum markers can reliably identify the metastatic phenotype. Given the fact that not all prostate tumors secrete or express PSA, there is a critical need to develop other markers to identify metastatic phenotypes and PSA negative PC subtypes.
Substantial evidence exists suggesting the role of neuroendocrine growth factors in regulation of AIPC cells. For example, neuroendocrine factors such as bombesin and vasoactive intestinal polypeptide have been shown to influence the invasive behavior of prostate cancer cell lines. Other factors not necessarily regarded as exclusively neuroendocrine in origin, but secreted by neuroendocrine cells such as epidermal growth factor and somatostatin, have also been shown to influence either the invasive characteristics or growth of prostate cancer cell lines. Pindobind, a serotonin Hla receptor antagonist, has been shown to inhibit the growth of prostate cancer cell lines. In addition, foci of neuroendocrine differentiation have been demonstrated in between 47% and 100% of prostate cancers using a combination of sensitive argyrophil staining and immunocytochemistry. Thus, it is likely that neuroendocrine factors play an important role in prostate cancer.
Grade of the cancer determines the severity of the cancer and varies from low to high grades. Low grade prostate tumor grows very slowly and often does not require any aggressive forms of therapy. However, high-grade prostate tumor grows and metastasizes aggressively and requires aggressive therapeutic intervention. Determination of the grade of prostate tumor is crucial for the choosing the right form of therapy. Present methods of determination of the grade of prostate cancer involve examination of the architecture of the prostate tumor in sections of biopsy. However, this method is prone to error due to the fact that there is considerable inter-observer variation leading to wrong diagnosis of the grade of the tumor. Determination of the grade of the tumor based on a biochemical marker rather than the visual observation of the architecture of the tissue would provide a better method for identifying the grade of the tumor. This has led to major efforts at identifying new biochemical markers for prostate cancer.
The present invention involves a novel neuroendocrine growth factor or marker (“NEM”) identified in cultured prostate cancer cells. A significantly higher number of binding sites for this novel NEM is present on membranes of prostatic cancer cells than on those of benign prostatic hypertrophy (BPH), a common benign enlargement of the prostate in older men. The ability to differentiate BPH from malignancy is highly important but cannot be effectively accomplished using PSA screening, the most commonly used method for detecting the presence of prostate cancer clinically. The limitations of PSA screening are overcome by screening patient blood for NEM which will identify metastatic prostate cancer, distinguish it from BPH, and can be used in excised tissues to identify the type of cancer and grade its degree of malignancy. Lastly, inhibition of NEM in turn decreases prostatic cancer growth, invasion and metastasis. As such, NEM antagonism offers new modes of therapy for prostate cancer. The data also shows that the expression of NEM in prostate cancer tissues increases with the grade of the cancer. While there is very little or no NEM expression of NEM in BPH (a non-cancerous condition) NEM expression can be seen in all prostate cancer tissues starting as early as the PIN stage, which is considered to be a precursor of invasive cancer. Hence the data shows that NEM is a good biochemical marker for prostate cancer.